Adding ustekinumab to SOC may improve SLE outcomes
The addition of ustekinumab to standard-of-care (SOC) treatment resulted in improved outcomes in adults with systemic lupus erythematosus (SLE) whose disease activity persisted despite standard treatment, according to a phase II trial.
A total of 102 patients aged 18–75 years with persistent moderate-to-severe SLE disease activity despite SOC treatment were randomized to receive an intravenous infusion of ustekinumab at week 0 (260, 390, and 520 mg for patients weighing 35–55, >55 to ≤85, and >85 kg, respectively) plus subcutaneous ustekinumab 90 mg at week 8 and every 8 weeks thereafter (n=60, mean age 40 years, 97 percent female, mean weight 75.4 kg) or an intravenous infusion of placebo at week 0, subcutaneous placebo at weeks 8 and 16, and crossed over to receive subcutaneous ustekinumab 90 mg at week 24 and every 8 weeks thereafter (n=42, mean age 42.9 years, 83 percent female, mean weight 74.3 kg) in addition to SOC treatment for up to 40 weeks.
Patients needed to have tested positive for autoantibodies, have a SLEDAI-2K* score of ≥6 during screening and ≥4 for clinical features at baseline while on SOC treatment, and at least one BILAG-2004** domain A or two BILAG domain B scores during screening to be included. Patients with other inflammatory conditions including unstable or progressive SLE were excluded.
At week 24, more patients on ustekinumab than placebo achieved a SLEDAI-2K responder index-4 (SRI-4)*** response (62 percent vs 33 percent, percentage difference, 28 percent; p=0.006). [Lancet 2018;doi:10.1016/S0140-6736(18)32167-6]
More patients on ustekinumab than placebo also experienced no worsening in BILAG-2004 score (48 percent vs 26 percent, percentage difference, 22 percent; p=0.028). However, BICLA# response was comparable between patients who received ustekinumab and placebo (35 percent vs 33 percent; p=0.994).
Patients on ustekinumab also had a greater SLEDAI-2K response rate compared with those on placebo (76.8 percent vs 49.1 percent; p=0.007). Incidence of disease flares between weeks 12 and 24 was lower among those who received ustekinumab than placebo (hazard ratio, 0.12; p=0.012), while reductions in the number of active joints at week 24 was comparable between treatment groups (p=0.103).
Seventy-eight and 67 percent of patients on ustekinumab and placebo, respectively, experienced at least one adverse event (AE) over the 24-week period. The most common AE was infections, experienced by 45 and 50 percent of patients in the ustekinumab and placebo groups, respectively, with urinary tract infections, nasopharyngitis, and upper respiratory tract infections the most frequently occurring ones. There were no incidences of tuberculosis, or treatment-emergent opportunistic infections, herpes zoster, or malignancies.
“Studies of B-cell-targeted therapies in SLE have had mixed results, standard therapies carry considerable toxicity, and only a single drug with a novel mechanism of action has been approved for SLE in almost 6 decades. Thus, a significant unmet need remains for these patients,” said the researchers.
“[T]he findings in this trial suggest clinically meaningful effects of ustekinumab on SLE disease activity and flares. Although the SRI-4 and BICLA responses were inconsistent in this study, the totality of the efficacy findings suggests that ustekinumab might benefit both global and organ-specific disease activity in SLE,” they said.
The outcomes now need to be assessed in a phase III trial which will include a larger patient population, they said. Another study is underway to identify the appropriate dosing indication of ustekinumab for SLE.
Importance of optimizing SOC
According to Professors Nathalie Costedoat-Chalumeau and Frédéric Houssiau from Cochin Hospital, Paris, France, and Cliniques Universitaires Saint-Luc in Brussels, Belgium, respectively, not all patients were receiving optimal SOC treatment, highlighting for example, the low number of methotrexate recipients despite many of them having active arthritis.
“How many patients might have attained an SRI-4 response at week 24 by optimizing SOC and by verifying and encouraging their adherence to therapy?” they asked in a commentary. [Lancet 2018;doi:10.1016/S0140-6736(18)32330-4]
“Although we very much hope that ustekinumab will fare better than so many other targeted therapies for SLE, we also strongly advise that all patients with SLE be treated according to the current excellent guidelines, with more attention to adherence to treatment and more systematic use of effective, widely available, and affordable drugs,” they said. They also hoped that if approved, ustekinumab could result in the reduction of steroid consumption, with its administration method potentially encouraging treatment adherence.